Long-term efficacy, safety, and tolerability of tocilizumab in rituximab-refractory rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is an inflammatory autoimmune process, and the dysregulated overproduction of interleukin-6 (IL-6) plays an important role in its pathogenesis. Tocilizumab (TCZ) is a humanized monoclonal antibody targeting the IL-6 receptor, and is recommended for use in RA. (1) There is evidence demonstrating good outcomes with TCZ in patients who have disease refractory to B-cell depletion with rituximab (RTX), a chimeric monoclonal antibody targeting CD20 B-cells, with up to 18 months' follow-up. (2) Long-term data, however, on the efficacy, safety and tolerability of TCZ in RA that is refractory to sDMARDs, anti-TNF and RTX are lacking. Objectives: To evaluate the long-term efficacy and safety of TCZ in real patients with RA refractory to synthetic DMARDs, anti-TNF agents and B cell depletion therapy with RTX, beyond 2 years. Methods: We retrospectively studied 45 patients from two centres who received TCZ for median 48-months (range, 9-72) duration. All patients received anti-TNF and RTX previously. Efficacy and safety was evaluated according to the EULAR response criteria and EMEA guidance, respectively. Wilcoxon matched ranks test was used to assess changes in outcomes. Results: Of 45 patients, 36 (80%) had previously discontinued RTX due to inefficacy and 9 (20%) due to intolerance. At most recent follow-up, median 48 months, 30 of 45 (67%) patients were continuing TCZ and 15 (33%) had discontinued, 7 due to inefficacy and 8 others due to intolerance. Of 36 patients with RTX-refractory RA, 25 (69%) were continuing TCZ and 11 had discontinued due to, inefficacy in 6 (17%) and intolerance in 5 (14%): 2 patients due to diverticulitis, 2 due to upper respiratory tract infections and 1 due to discitis. Of the 9 patients with RTX-intolerance, 5 (56%) were continuing TCZ and 4 (44%) had discontinued: 1 patient due to inefficacy and 3 due to intolerance, who had a prior history of hypogammaglobulinemia and infections associated with RTX. There were no significant differences in lipid profile in 25 of 36 of patients continuing TCZ therapy whereas 11 required statin therapy. Conclusions: A majority of patients with RA refractory to synthetic DMARDs, anti-TNF and RTX responded to TCZ. Lipid profile in a majority of patients was stable in the long-term. Key messages: 1. The efficacy of TCZ is sustained in the long-term in patients with RTX-refractory RA. 2. TCZ appears to be safe in patients previously treated with RTX. TCZ does not alter lipid profile in a majority of the patients with RTX-refractory RA.